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The current emphasis is to describe and understand the defects in natural killer (NK) cell function in a group of patients with Chediak-Higashi syndrome (CHS). We analyzed NK cells in PBMCs of two CHS patients with the active disease, their healthy immediate family members, as well as one CHS patient that underwent bone marrow transplantation. We found that the two CHS patients have slightly lower, but close to normal percentage of NK cells (2% and 3.3% for patient 1 and 2, vs. 4.39% and 4.06% for parents). The levels of the investigated activating and inhibitory NK cell surface receptors were normal and there was no difference between receptor levels in the two patients when compared to their family members or unrelated healthy individual, indicating that the disease is not affecting the trafficking of NK cell surface receptors. In addition, the intracellular levels of critical components of lytic granules, perforin and granzyme B, were very similar between family members. When compared to the healthy family members, however, NK cells from CHS patients had severely decreased cytotoxic potential, due to impaired degranulation ability. Intriguingly, the defect of release of the lytic granules was not observed in case of cytokine production and secretion. When compared to their parents, the two CHS patients have similar level of up-regulation of MIPb;and TNFa;in response to cytokine stimulation. Moreover, the cytokine stimulation resulted in more robust IFNg;production by NK cells of both patients (67-69% of NK cells in patients vs. 40 53% in parents). In comparison, NK cells from the CHS patient that received a bone marrow transplant appeared to be normal and the levels of the cell surface expression of NK cell activating and inhibitory receptors were comparable to those of healthy individuals. NK cells of the transplanted patient conjugated with target cells normally and the killing of two different target cell lines was comparable to NK cells from a healthy individual. Furthermore, NK cells of the transplanted patient readily polarized perforin and granzyme A to the cell-cell contact site. Interestingly, when compared to a healthy donor, NK cells of the transplanted patient showed increased degranulation in response to engagement of CD16 (27% vs 10% of the healthy donor) and, consequently, ADCC was increased in case of the transplanted patient. In response to cytokine stimulation, the production of MIP-1b, IFNg and TNFa by NK cells from the transplanted CHS patient was comparable to that of NK cells from a healthy donor. Thus, the bone marrow transplant fully restored NK cell functionality in this patient.